1. Field of the Invention
The present invention relates to a surface plasmon resonance (SPR) sensor, and in particular, to an optical waveguide SPR sensor.
2. The Prior Arts
Physiological phenomenon of organisms often includes many very complicated biochemical reaction mechanisms. Such biochemical reaction mechanisms often involve interactions of macromolecules with other molecules. Therefore, many analysis methods and tools are provided to detect the reactions of the macromolecules for the purpose of understanding such complex reaction mechanisms.
Among so many analysis methods and tools, biosensors based on surface plasmon resonance (SPR biosensor) gradually attract more attention. Since 1990, there have been many manufactures producing the SPR biosensors. The manufacturers are listed in table 1 recited below, given by McDonnell, Chemical Biology (2001) 5:572-577.
TABLE 1Manufactures of SPR SensorsManufactures and their WebsitesProductBIAcore AB (Uppsala, Sweden)BIAcorehttp://www.biacore.comAffinity Sensors (Franklin, MA)IASyshttp://www.affinity-sensors.comNippon Laser Electronics (Hokkaido, Japan)SPR-670http://www.rikei.comArtificial Sensing Instruments (Zurich, Switzerland)OWLShttp://www.microvacuum.com/products/biosensorIBIS Technologies BV (Enschede, The Netherlands)IBIShttp://www.ibis-spr.nlTexas Instruments (Dallas, TX)TISPRhttp://www.ti.com/spreetaAviv (Lakewood, NJ)PWR-400http://www.avivinst.comBioTul AG (Munich, Germany)Kinomicshttp://www.biotul.comQuantech Ltd (Eagan, MN)FasTraQhttp://www.quantechltd.com
In general, SPR biosensors have the advantages of high sensitivity, labeling free to the analyte, fast testing, and adapted for real-time analysis of interactions between molecules, quantitative analysis, and mass parallel screening. They are also practically applied to detect intermolecular reactions between, for example, antigens and antibodies, enzyme and its substrate, hormone and its receptor, as well as nucleic acid and nucleic acid. An SPR biosensor can also be incorporated with a biochip to set up a new drug screening platform. Further, a sensor based on SPR is also applicable for analytical chemistry, environmental engineering, or even military purpose.
The underlying physical principle of SPR is that when a light beam incident to a surface of a metal film with a certain incident angle, an intensity of reflected light beam detected by a light detector approaches zero. In other words, a reflectivity of the metal film approximates to zero. The unreflected light becomes an evanescent wave, and is transmitted along a direction parallel with the interface with a certain speed. Such an evanescent wave excites an SPR at the surface of metal film, and the phenomenon is known as an attenuated total reflection (ATR).
A conventional SPR sensor conducts measurements according to the foregoing principle. Such a conventional SPR sensor usually includes a thin metal layer and a sensing region adjacent to the thin metal layer. The thin metal layer is often configured on a dielectric prism or grating. The dielectric prism or grating is used as an optical coupler for exciting SPR. With such a conventional SPR sensor is operated to measure an analyte, the analyte is carried through the sensing region, and a light beam is incident the prism or the grating and arrives a surface of the thin metal layer. An intensity of reflected light at the surface of the thin metal layer is measured. As the matter sensed at the sensing region of the SPR sensor changes, correspondingly detected SPR characteristics also change. In this manner, interactions between different matters or concentration of a certain matter can be measured by measuring the certain angle at which the light reflectivity sharply attenuates.
However, the foregoing SPR sensor measures mainly by modulating the incident angle of the incident light and measuring a corresponding intensity change of the reflected light, so that the resolution and sensitivity thereof are restricted by the angle range of the incident light which excites the SPR. In another hand, the incident angle of the incident light for exciting the SPR is also related to a wavelength thereof. As such, when the wavelength varies, it causes errors of the measurement.
Another typical SPR utilizes optical waveguide as the optical coupler. This SPR sensor includes a thin metal layer and a sensing region adjacent to the thin metal layer. The thin metal layer is configured on an optical waveguide. After incident in the optical waveguide, when a component of the wave vector of the incident light at a direction parallel with the interface equals to a wave vector of a surface plasmon wave, an SPR is then excited, and thus causing a light intensity attenuation at an output end of the optical waveguide. Dielectric indices of respectively the analyte and the thin metal layer determine the wave vector of the surface plasmon wave, and therefore, when the analyte varies, the dielectric index thereof changes correspondingly. As such, interactions between different matters or concentration of a specific matter can be measured by measuring a characteristic wavelength or an attenuation of light intensity when SPR occurs.
The optical waveguide SPR sensor is usually adapted for two measurement modes for measuring analyte. The first mode is utilizing a light source of a specific wavelength and measuring an attenuation of the light intensity. The second mode is utilizing a white light having a continuous wave frequency spectrum to measure a characteristic wavelength of which a light intensity sharply attenuates. As such, the resolution and sensitivity of the optical waveguide SPR sensor are not restricted by the range of the incident angle of the incident light at which the SPR is excited. Further, the optical waveguide SPR sensor is convenient for integration which requires only a little sample for precision measurement, and thus is more applicable.
A conventional optical waveguide SPR sensor has been disclosed by Yutaka Ohmori et al., Thin Solid Films, 393, 267-272, 2001, and J. Dostalek et al., Sensors and Actuators B, 76, 8-12, 2001. This optical waveguide SPR sensor is configured by a method including: disposing a metal film having a waveguide pattern on a substrate by an optical etching or a coating process; and then implementing ions to the substrate by a high temperature ion exchanging process to change the refractive index of the substrate, and thus obtaining an optical waveguide. In order to attaining the SPR, a metal layer and a dielectric layer used for adjusting a sensing range are further required to be disposed on the waveguide by a semiconductor processing as a SPR sensing region. This conventional optical waveguide SPR sensor is generally a single channel optical waveguide SPR sensor, which has only sensing region on the optical waveguide. As such, it is incapable of providing a multi-sample measurement or a reference differential measurement. Therefore, errors of the measurement result obtained by this conventional optical waveguide SPR sensor are still relatively large.
Furthermore, another optical waveguide SPR sensor is proposed by R. D. Harris et al., Biosensors & Bioelectronics 14 (1999) 377-386. Although this optical waveguide SPR sensor includes a reference arm, the optical waveguide is designed as Y-shape bifurcated. Unfortunately, this causes uneven light distribution and unwanted light attenuation, which are difficult to overcome in considering the processing precision and cost.